This revised competitive renewal of a longitudinal study of brain and behavioral development in young boys with Fragile X Syndrome (FXS), entitled Longitudinal MRI Study of Brain Development in Fragile X (RO1 MH64708), proposes continuation of a highly successful, collaborative study conducted by research teams at Stanford University (PI: Allan Reiss) and the University of North Carolina (PI: Joe Piven). FXS is an etiologically homogeneous developmental disorder and the most common single gene disorder associated with autistic behavior. Data from the initial grant cycle reveal a pattern of behaviors in FXS that differ from that seen in idiopathic autism (iAUT), with (a) prominent lower-order restricted, repetitive behaviors (RRB) such as perseveration, motor stereotypies and repetitive language; (b) less severe (than in iAUT) higher order RRB such as compulsions and rituals, and (c) less severe social and other communication deficits. Contrasting the pattern seen in iAUT, RRB show increasing severity over time and is significant association with functional impairment in individuals with FXS. This prominence of RRB in FXS is accompanied by parallel findings from MRI/DTI showing striking developmental abnormalities in striato-frontal and thalamo-frontal neural circuitry. Taken together these findings suggest that the emergence of abnormalities in striato-frontal and thalamo- frontal neural circuitry underlie the development of abnormalities in lower-order repetitive behaviors that have a prominent, negative impact on the function of children with FXS as they reach the school-age period. Clarification of the nature and timing of emergence of these brain and behavior abnormalities will be of critical importance in designing novel therapeutics for FXS and related disorders, and in measuring the efficacy of such interventions. We therefore propose a comprehensive battery to characterize RRB and striato- frontal/thalamo-frontal neuroanatomy (employing state-of-the-art MRI and diffusion tensor imaging), in 50 school-aged boys with FXS, 50 school-aged boys with iAut, 30 developmentally-delayed (non-syndromic, non- autistic) and 35 typically-developing boys at 7 - 12 years of age. These children received longitudinal brain and behavior assessments at 1-3 and, 24 months later at 3-5 years of age during the initial grant period. Perseverative, repetitive behaviors are typically cited as being among the most disruptive aspects of FXS and are commonly a primary focus of treatment in both iAUT and FXS. However, the phenomenology and neurobiology of RRB in FXS is an area that has received little research attention. This study thus provides a unique opportunity to elucidate the neurobiological basis and development of RRB in FXS and related disorders, and promises to generate results that will impact studies of pathogenesis and treatment as well as provide insights into the neurobiological basis of autistic behavior. PUBLIC HEALTH RELEVANCE: A Longitudinal MRI Study of Brain Development in Fragile X is a proposal to study restricted, repetitive behaviors (RRB) in 7-12 year old boys with fragile X syndrome (FXS), using magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and a battery of assessments designed to evaluate repetitive behaviors (such as perseveration, motor stereotypes, and repetitive language). These repetitive behaviors are typically reported by families as being among the most disruptive aspects of FXS and are commonly a primary focus of treatment in both FXS and autism. This study will provide a unique opportunity to understand the neurobiological basis and development of RRB in FXS and related disorders, which will have important implications for treatment.